Plymouth University - Dr Oleg Anichtchik

Scientific title: Examining effects of an interaction between α- and β-synucleins in dementia with Lewy bodies

Type of project: Pilot study

What do we already know?

Dementia with Lewy bodies (DLB) is characterised by the accumulation of a protein called α-synuclein into deposits known as Lewy bodies in the parts of the brain are associated with memory. This may lead to neurodegeneration in these brain regions. Another member of the same protein family, β-synuclein, has been shown to have anti-aggregating effects over α-synuclein in a Petri dish.

What is this project trying to find out?

This project aims to investigate how levels of β-synuclein are associated with α-synuclein aggregation and Lewy body formation, resulting in brain cell damage in DLB patients.

How will they do this?

Human post-mortem brain tissue already obtained from a brain bank will be used in this study. Cells containing Lewy bodies will be extracted from the tissue and the levels of β-synuclein gene expression, together with other pathways thought to be involved in dementia, will be examined to see the relationship with α-synuclein aggregation.

Why is it important?

If a direct relationship is found between α- and β-synuclein, then β-synuclein could be targeted to prevent α-synuclein aggregation, which may in turn slow the progression of DLB in patients. This could potentially be extended to other pathologies involving α-synuclein aggregates such as Parkinson’s disease.

A protein known as α-synuclein is found in all neurons in the brain, and if it forms clumps (aggregates) it can damage cellular functions and result in cell death. These α-synuclein aggregates are present in the brains of patients with dementia with Lewy bodies (DLB), and are responsible for the clinical symptoms of this disease.

Synapses are the chemical junctions between neurons, and the high energy demands of this area mean that mitochondria are present in abundance. Mitochondria are the main energy factory for cells, and are highly mobile structures that can merge or split depending on the energy demands of the cell (a process known as mitochondrial dynamics). Evidence of enhanced mitochondrial breakdown has been shown in post mortem DLB brain samples, and it is thought that α-synuclein aggregation at synaptic sites leads to their mitochondrial fragmentation and thus dysfunctional dynamics, ultimately contributing to the pathology of DLB.

What is this project trying to find out?

This project aims to examine the α-synuclein-associated alterations in mitochondrial dynamics in the brains of DLB patients and, using neuronal model cell lines, the mechanisms involved in mitochondrial dynamic dysfunction in DLB. Moreover, the group will investigate whether promoting mitochondrial fusion (or blocking fission) will protect against the neurotoxic effects of α-synuclein aggregation.

How do they do this?

Healthy and DLB human post mortem tissue samples will be examined for markers of altered mitochondrial dynamics and lysosomal degradation pathways. Genotyping, mitochondrial imaging techniques and measures of mitochondrial activity in a neuronal cell line that can be induced to accumulate α-synuclein will support this work. This cell line will also be treated with blockers of mitochondrial fission to assess whether this improves neuronal survival.

Why is it important?

This research will open up the new avenue of research in DLB and will provide indications for novel therapeutic interventions to improve symptoms and to prevent the neuronal loss observed in DLB.